WO2008041966A2 - Broad spectrum antibacterial compounds - Google Patents

Broad spectrum antibacterial compounds Download PDF

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Publication number
WO2008041966A2
WO2008041966A2 PCT/US2006/031550 US2006031550W WO2008041966A2 WO 2008041966 A2 WO2008041966 A2 WO 2008041966A2 US 2006031550 W US2006031550 W US 2006031550W WO 2008041966 A2 WO2008041966 A2 WO 2008041966A2
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Prior art keywords
nsc
compound
amidine
bacteria
compounds
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PCT/US2006/031550
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French (fr)
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WO2008041966A3 (en
Inventor
Sina Bavari
Rekha G. Panchal
Rick Gussio
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United States Government As Represented By The Secretary Of The United States Army And The U.S. Army Medical Research & Materiel Command
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Application filed by United States Government As Represented By The Secretary Of The United States Army And The U.S. Army Medical Research & Materiel Command filed Critical United States Government As Represented By The Secretary Of The United States Army And The U.S. Army Medical Research & Materiel Command
Priority to JP2008537701A priority Critical patent/JP5390186B2/en
Priority to EP06851682.2A priority patent/EP1945209B1/en
Priority to CA2617123A priority patent/CA2617123C/en
Priority to AU2006345003A priority patent/AU2006345003A1/en
Publication of WO2008041966A2 publication Critical patent/WO2008041966A2/en
Publication of WO2008041966A3 publication Critical patent/WO2008041966A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds which exhibit antibacterial properties.
  • the present invention relates to compounds which exhibit antibacterial properties.
  • the compounds of the present invention have the following structural formula:
  • n 1 or 2;
  • L is a linker which may be a direct bond or ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
  • R 8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 290111 , NSC 302569, and NSC 308569.
  • at least one of R 1 , R 2 , R 3 , or R 4 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine.
  • R 6 is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl- imidazoline, benzofuran-2-yl-amidine, benzofuran-2-yl-guanidine, benzothiophene-2- yl-imidazoline, benzothiophene-2-yl-amidine, benzene-2-yl-amidine, benzofuran-2- yl-imidazole, or benzofuran-2-yl-oxazole.
  • At least one of X 1 or X 2 is N, NH, S, O, SO 2 , CH, C-CH 3 , C-phenyl, N-ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5-amidine).
  • at least one of X 3 , X 4 , X 5 , or X 6 is N, NH, S, O, SO 2 , or CH.
  • R 7 is -H, -CH 3 , -NH 2 , .
  • R is -NH 2 ,
  • R 8 is -H, -(CH 2 )2 ⁇ H, or -(CH 2 ) 2 C1.
  • L is a direct bond, has the following structural formulae:
  • the compound is NSC 92833, NSC 103699, NSC 103701, NSC 130681, NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240896, NSC 240897, NSC 240898, NSC 240899, NSC 240900, NSC 266472, NSC 266474, NSC 266475, NSC 266476, NSC 266477, NSC 266482, NSC 278995, NSC 278996, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290109, NSC 291103, NSC 294199, NSC 294200, NSC 294201, NSC 294202, NSC 294203, NSC 294204, NSC 294206, NSC 294207, NSC 294208, NSC 294494, NSC 300509, NSC 300510, NSC 300511, NSC 300512, NSC 308570, N
  • the compound is NSC 317880, NSC 317881, NSC 330687, or NSC 369718.
  • the present invention provides a method of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain which comprises contacting the bacteria with an effective amount of at least one compound provided herein.
  • the bacterial strain is belongs to Bacillus, Burkholderia, Enterobacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia, or drug resistant strains thereof.
  • the bacterial strain is B. anthracis, B. brevis, B. licheniformis, B. megaterium, B. pumilus, B.
  • the bacteria are of two or more bacterial strains.
  • the bacteria are on or in an object, such as clothing, a table top, eating utensils, water, food, air, or anything which may come into contact with or may be consumed by a mammal such as a human.
  • the present invention provides a method of treating, inhibiting or preventing an infection or intoxication caused by bacteria of at least one bacterial strain in a subject which comprises administering to the subject a therapeutically effective amount of at least one compound provided herein.
  • the bacterial strain is belongs to Bacillus, Burkholderia, Enter obacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia, or drug resistant strains thereof.
  • the bacterial strain is B. anthracis, B. brevis, B. licheniformis, B.
  • the bacteria are of two or more bacterial strains.
  • the compound is in the form of a pharmaceutical or cosmetic composition.
  • a supplementary active compound is administered to the subject.
  • the supplementary active compound may be formulated with a compound of the present invention or provided as a separate composition.
  • Figure IAl shows a phase contrast image of GFP-sterne spores that were treated with a DMSO control and the growth of vegetative cells after 22 hours.
  • Figure 1 A2 shows a GFP fluorescence image of GFP-sterne spores that were treated with a DMSO control and the growth of vegetative cells after 22 hours.
  • Figure IBl shows a phase contrast image of GFP sterne spores treated with
  • Figure 1B2 shows a GFP fluorescent image of GFP sterne spores treated with
  • NSC 317881 (MIC of 0.084 ⁇ g/ml) for 22 hours.
  • Figure 1 C is a graph showing time dependent inhibition of GFP fluorescence by a few compounds of the present invention at their MIC concentrations.
  • Figure ID is a graph showing growth inhibition of GFP sterne vegetative cells at different concentrations of a few compounds of the present invention.
  • Figure 2 is a graph which shows that NSC 317881 does not have any observable effect on sterne spore germination.
  • Figure 3 is a graph which shows that NSC 317881 kills GFP sterne spores in a time dependent manner.
  • Figure 4 shows the structural formulas of NSC 317880, NSC 317881, NSC
  • the present invention is directed to the antibacterial properties of bi- and triarylimidazoiidines and bi- and triarylamidines.
  • the compounds of the present invention do not structurally resemble any of the current classes of clinically used antibiotics, including penicillins, cephalosporins, monobactams, carbapenems, fluoroquinolones, macrolides, aminoglycosides, streptogramins, oxazolidinones, metronidazole, clindamycin, and vancomycin.
  • the compounds of the present invention are active against a broad range of gram positive and gram negative bacteria, including drug resistant strains such as vancomycin resistant enterococcus, methicillin resistant Staphylococcus aureus (MRSA) and ciproflaxcin resistant B. anthracis. As provided herein, some of the compounds of the present invention exhibit MIC values ranging from about 0.021 to about 22 ⁇ g/ml. Some of the compounds exemplified herein inhibit the outgrowth of B. anthracis spores and kill B. anthracis vegetative spores in the early stages of germination.
  • drug resistant strains such as vancomycin resistant enterococcus, methicillin resistant Staphylococcus aureus (MRSA) and ciproflaxcin resistant B. anthracis.
  • MRSA methicillin resistant Staphylococcus aureus
  • ciproflaxcin resistant B. anthracis ciproflaxcin resistant B.
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, S, O, SO 2 , CR 7 or NR 8 and at least one of X 1 or X 2 is N, S, O, SO 2 , or NR 8 ;
  • L is a linker which may be a direct bond or ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
  • the bond orders of the specified rings may vary when the various heteroatoms introduce specific requirements to satisfy aromaticity, prevent antiaromaticity, and stabilize tautomeric forms due to localization.
  • the appropriate bond orders of the ring structures in the structural formulas of the present invention are contemplated herein.
  • R 1 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine.
  • R 6 is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl- imidazoline, benzofuran-2-yl-amidine, benzofuran-2-yl-guanidine, benzothiophene-2- yl-imidazoline, benzothiophene-2-yl-amidine, benzene-2-yl-amidine, benzofuran-2- yl-imidazole, or benzofuran-2-yl-oxazole.
  • X 1 is N, NH, S, O, SO 2 , CH, C-CH 3 , C-phenyl, N- ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5 -amidine).
  • X 3 is N, NH, S, O, SO 2 , or CH.
  • X 4 is N, NH, S, O, SO 2 , or CH.
  • X 6 is N, NH, S, O, SO 2 , or CH.
  • At least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 is -H, -CH 3 ,
  • R is -NH 2 , H,
  • R is or
  • R 8 is -H, -(CH 2 ) 2 OH, or -(CH 2 ) 2 C1.
  • L is a direct bond
  • compounds of the present invention have the following structural formulae:
  • n 1 or 2;
  • L is a linker which may be a direct bond or ⁇ ⁇ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
  • R 8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 2901 11, NSC 302569, and NSC 308569.
  • a "halo” or “halogen” means fluorine, bromine, chlorine, and iodine.
  • alkyl is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (n-Bu), isobutyl (i-Bu), t- butyl (t-Bu), (sec-Bu), and the like, which may be unsubstituted (i.e., contain only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
  • a "lower alkyl group” is intended to mean an alkyl group having from 1 to 8 carbon atoms in its chain.
  • haloalkyl refers to an alkyl that is substituted with one or more same or different halo atoms, e.g., -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CCl 3 , and the like.
  • alkenyl means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one double bond such as ethenyl, 3-buten-l-yl, 2- ethenylbutyl, 3-hexen-l-yl, and the like.
  • alkenyl includes, cycloalkenyl, and heteroalkenyl in which 1 to 3 heteroatoms selected from O, S, N or substituted nitrogen may replace carbon atoms.
  • alkynyl means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one triple bond and includes, but is not limited to, ethynyl, 3-butyn-l-yl, propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like.
  • a "cycloalkyl” is intended to mean a non-aromatic monovalent monocyclic or polycyclic radical having from 3 to 14 carbon atoms, each of which may be saturated or unsaturated, and may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be unsubstituted or substituted by one or more substituents.
  • cycloalkyl groups include cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl.
  • heterocycloalkyl is intended to mean a non-aromatic monovalent monocyclic or polycyclic radical having 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be unsubstituted or substituted by one or more substituents.
  • heterocycloalkyl groups include oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholinyl.
  • aryl is intended to mean an aromatic monovalent monocyclic or polycyclic radical comprising generally between 5 and 18 carbon ring members, which may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl group includes a benzyl group (BzI). Examples include phenyl, biphenyl, 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl, and phenanthryl.
  • a "heteroaryl” is intended to mean an aromatic monovalent monocyclic or polycyclic radical comprising generally between 4 and 18 ring members, including 1-
  • heteroatoms selected from nitrogen, oxygen, and sulfur which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • Examples include thienyl, furanyl, thiazolyl, triazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrrolyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl, pyrimidinyl, isoquinolinyl, quinolinyl, napthyridinyl, phthalimidyl, benzimidazolyl, and benzoxazolyl.
  • a "hydroxy" is intended to mean the radical -OH.
  • alkoxy is intended to mean the radical -OR, where R is an alkyl group.
  • alkoxy groups include methoxy, ethoxy, propoxy, and the like.
  • a "hydroxyalkyl” means an alkyl that is substituted with one, two, or three hydroxy groups, e.g. hydroxy methyl, 1 or 2-hydroxyethyl, 1,2-, 1,3-, or 2,3- dihydroxypropyl, and the like.
  • a "haloalkoxy” refers to an -O-(haloalkyl) group. Examples include trifluoromethoxy, tribromomethoxy, and the like.
  • a "cycloalkoxy” is intended to mean the radical -OR, where R is acycloalkyl or heterocycloalkyl group.
  • An "aryloxy” is intended to mean the radical -OR, where R is an aryl or heteroaryl group. Examples include phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like.
  • An "acyl” is intended to mean a -C(O)-R radical, where R is an alkyl or aryl, bonded through a carbonyl group. Acyl groups include acetyl, benzoyl, and the like.
  • An “aralkyl” means an alkyl that is substituted with an aryl group.
  • a "heteroaralkyl” group means an alkyl that is substituted with a heteroaryl group. Examples include -CH 2 -pyridinyl, -(CH 2 ) 2 -pyrimidinyl, -(CH 2 ) 3 -imidazolyl, and the like.
  • a "carboxy” is intended to mean the radical -C(O)OH.
  • An "alkoxycarbonyl” is intended to mean the radical -C(O)OR, where R is an alkyl group. Examples include methoxycarbonyl, ethoxycarbonyl, and the like.
  • An "amine with stabilized carbocations" are comprised of two or more NH 2 groups that contribute lone pairs to configure a highly stabilized carbocation. Examples include amidines and guanidines.
  • alkylamino is intended to mean the radical -NHR, where R is an alkyl group or the radical -NR a R b , where R a and R b are each independently an alkyl group.
  • alkylamino groups include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino, N- n-hexyl-N-methylamino and the like.
  • Examples include methylsulfhydryl, ethylsulfhydryl, n-propylsulfhydryl, iso- propylsulfhydryl, n-butylsulfhydryl, iso-butylsulfhydryl, secondary-butylsulfhydryl, tertiary -butylsulfhydryl.
  • Preferable alkylsulfhydryl groups are methylsulfhydryl, ethylsulfhydryl, n-propylsulfhydryl, n-butylsulfhydryl, and the like.
  • alkylhydroxymate is intended to mean the radical R-C(O)NH-OH, where R is an alkyl group. Examples include methylhydroxymate, ethylhydroxymate, n-propylhydroxymate, iso-propylhydroxymate, n-butylhydroxymate, iso- butylhydroxymate, secondary-butylhydroxymate, tertiary-butylhydroxymate. Preferable alkylhydroxymate groups are methylhydroxymate, ethylhydroxymate, n- propylhydroxymate, n-butylhydroxymate, and the like.A "carbamoyl” is intended to mean the radical -C(O)NH 2 .
  • alkylaminocarbonyl is intended to mean the radical -C(O)NHR, where
  • R is an alkyl group or the radical -C(0)NR a R b , where R a and R b are each independently an alkyl group. Examples include methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, methylethylaminocarbonyl, and the like.
  • a "mercapto" is intended to mean the radical -SH.
  • alkylthio is intended to mean the radical -SR, where R is an alkyl or cycloalkyl group.
  • alkylthio groups include methylthio, ethylthio, n- propylthio, isopropylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • arylthio is intended to mean the radical -SR, where R is an aryl or heteroaryl group. Examples include phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
  • a "thioacyl” is intended to mean a -C(S)-R radical, where R is an alkyl or aryl, bonded through a thiol group.
  • alkylsulfonyl is intended to mean the radical -SO 2 R, where R is an alkyl group. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso- propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, secondary-butylsulfonyl, tertiary- butylsulfonyl.
  • Preferable alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, n-butylsulfonyl, and the like.
  • a "protecting group” is intended to refer to groups that protect one or more inherent functional group from premature reaction. Suitable protecting groups may be routinely selected by those skilled in the art in light of the functionality and particular chemistry used to construct the compound. Examples of suitable protecting groups are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons, New York, New York (1999).
  • suitable organic moiety is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds.
  • suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxyl groups, carboxyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
  • carbocyclic cycloalkyl which may be monocyclic or fused or non- fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridiny
  • Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH 2 -O. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroarylthio groups, and the like.
  • groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl
  • Some of the compounds of the present invention may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both when they contain one or more stereogenic centers as designated by R or S according to the Cahn-Ingold-Prelog rules whether the absolute or relative configuration is known. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
  • Some of the compounds in the present invention may exist as geometric isomers as the result of containing a stereogenic double bond. In such cases, they may exist either as pure or mixtures of cis or trans geometric isomers or (E) and (Z) designated forms according to the Cahn-Ingold-Prelog rules and include compounds that adopt a double bond configuration as a result of electronic derealization.
  • an optically pure compound having one or more chiral centers is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
  • the compounds of the present invention may be used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
  • solvates are intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone.
  • miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture.
  • the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone.
  • the structural formulas include compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.
  • the compounds of the invention also include active tautomeric and stereoisomeric forms of the compounds of the present invention, which may be readily obtained using techniques known in the art.
  • active tautomeric and stereoisomeric forms of the compounds of the present invention may be readily obtained using techniques known in the art.
  • optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
  • the compounds of the invention include pharmaceutically acceptable salts, multimeric forms, prodrugs, active metabolites, precursors and salts of such metabolites of the compounds of the present invention.
  • salts refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being treated with the compound of the invention.
  • Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases.
  • Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid.
  • inorganic acids such as hydrochloric acid, hydro
  • Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g. , sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from non-toxic organic bases such as basic amino acids.
  • ammonium hydroxides e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide
  • inorganic bases such as alkali or alkaline earth-metal (e.g. , sodium, potassium, lithium, calcium, or magnesium) hydroxides
  • non-toxic organic bases such as basic amino acids.
  • multimer refers to multivalent or multimeric forms of active forms of the compounds of the invention. Such “multimers” may be made by linking or placing multiple copies of an active compound in close proximity to each other, e.g., using a scaffolding provided by a carrier moiety. Multimers of various dimensions (i.e., bearing varying numbers of copies of an active compound) may be tested to arrive at a multimer of optimum size with respect to binding site interactions. Provision of such multivalent forms of active binding compounds with optimal spacing between the binding site moieties may enhance binding site interactions. See e.g. Lee et al., (1984) Biochem. 23:4255. The artisan may control the multivalency and spacing by selection of a suitable carrier moiety or linker units.
  • Useful moieties include molecular supports comprising a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention.
  • a variety of carrier moieties may be used to build highly active multimers, including proteins such as BSA (bovine serum albumin), peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like, as well as non-biological compounds selected for their beneficial effects on absorbability, transport, and persistence within the target organism.
  • Functional groups on the carrier moiety such as amino, sulfhydryl, hydroxyl, and alkylamino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
  • a pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound, or a compound that is biologically active with respect to the intended pharmacodynamic effect.
  • a pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art See, e.g., Bertolini, G. et ah, (1997) J. Med. Chem. 40:2011-2016; Shan, D. et al, J. Pharm.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from basic amino acids, such as lysine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of the present invention are useful in inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain.
  • the compounds of the present invention are also treating, inhibiting or preventing an infection or intoxication caused by bacterial of at least one bacterial strain in a subject.
  • the bacteria belong to various gram positive and gram negative bacteria strains including Bacillus, Burkholderia, Enterobacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia and the like, including drug resistance strains.
  • the bacteria is B.
  • anthracis including Ames strain and ciprofloxacin resistant Ames strain
  • B. anthlO24 K1021
  • B. brevis including Ames strain and ciprofloxacin resistant Ames strain
  • B. licheniformis including Ames strain and ciprofloxacin resistant Ames strain
  • B. megaterium including Ames strain and ciprofloxacin resistant Ames strain
  • B. cepacia B. mallei, M. pseudomallei, and B. thailandensis
  • K. pneumoniae P. aeruginosa, preferably PAOl
  • & aureus and methicillin resistant S. aureous Y. pestis; or a combination thereof.
  • the activity of the compounds of the present invention may be measured by any of the methods available to those skilled in the art, including in vitro and in vivo assays. Examples of suitable assays for activity measurements are provided herein. Properties of the compounds of the present invention may be assessed, for example, by using one or more of the assays set out in the Examples below. Other pharmacological methods may also be used to determine the efficacy of the compounds a subject suffering from a given disease or disorder. The compounds of the present invention may be used in combination with or as a substitution for treatments known in the art.
  • the therapeutically effective amounts of the compounds of the invention for treating the diseases or disorders described above in a subject can be determined in a variety of ways known to those of ordinary skill in the art, e.g. by administering various amounts of a particular compound to a subject afflicted with a particular condition and then determining the effect on the subject.
  • therapeutically effective amounts of a compound of the present invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.
  • a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.
  • Frequency of dosage may also vary depending on the compound used and the particular disease treated It will also be appreciated that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances chronic administration may be required.
  • the compounds of the present invention may be administered before, during, after, or a combination thereof exposure to bacteria.
  • the pharmaceutical formulations of the invention comprise at least one compound of the present invention and may be prepared in a unit-dosage form appropriate for the desired mode of administration.
  • the pharmaceutical formulations of the present invention may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), dermal, mucosal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen compound of the present invention.
  • compositions of this invention comprise a therapeutically effective amount of at least one compound of the present invention, and an inert, pharmaceutically or cosmetically acceptable carrier or diluent.
  • pharmaceutically acceptable carrier or a “cosmetically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical or cosmetic administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the formulation is contemplated.
  • Supplementary active compounds can also be incorporated into the formulations.
  • Supplementary active compounds include antibiotics, antiprotozoal agents, antifungal agents, and antiproliferative agents known in the art, analgesics and other compounds commonly used to treat diseases and disorders associated with bacterial infection and toxic side effects of bacterial infection including intoxication by a toxin.
  • Antibiotics include penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolone, ciprofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimeth, trim
  • Antiprotozoal agents include chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine,
  • Antifungal agents include amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, and the like.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 0 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC5 0 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC5 0 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography. High throughput screening of small molecules against GFP-sterne spores and vegetative cells
  • Cipro resistant Ames 0.584 1.292 1.103 0.348
  • B. anthracis spores germinate within minutes following contact with a suitable medium, e.g. the moist tissue of the human respiratory system. Spore germination is usually detected in vitro by alterations in the spore refractility, heat resistance, and staining. Upon germination, spores will become non-refractile, increasing phase dark, susceptible to heat induced death, and stainable with dyes such as Wright-Giemsa stain. To determine the effects of the compounds on spore germination, NSC 317881 was selected for further study.
  • Sterne spores were germinated in Muller Hinton medium in the presence of DMSO (control) or NSC 317881 (1 ⁇ M). At time intervals of 0, 15, and 30 minutes, samples were heated at 65 °C for 30 minutes and after cooling on ice, appropriate dilutions of the spores were plated on sheep blood agar plates. The next day, colonies were counted. The % survival was determined by comparing the colony count at different time points to that of the sample collected at time to. Figure 2 shows the percent survival plotted against time. [115] Spores treated with NSC 317881 were killed by heat within 15 minutes following their contact with suitable germination medium, thereby suggesting that spore germination is not affected by the compound.
  • Cipro resistant Ames 1.168 1.292 4.41 0.348
  • the MBC was defined as 1 :he lowest concentration that produced a 99.9% reduction in viable count
  • NSC 317880, NSC 317881 and NSC 330687 are often referred to as diarylimidazolines, as each possesses two indoles, with each of the indoles substituted with an imidazolyl at its six position.
  • NSC 317880, NSC 317881 and NSC 330687 are a congeneric series that canvasses the structure-activity relationship of related structures.
  • the type of linker (see Structural Formula I) can result in structural differences that translate into large MIC variations from one bacterial species to another bacterial species.
  • NSC 369718 is often referred to as a triarylimidazoline which comprises two indoles and one benzofuran. As with the other three compounds, the imidazolyl substitutions occur at the six positions. See Figure 4.
  • these compounds exhibit common structural features, including a planar tertiary structure and indoles/furan rings that are substituted with two ionizable imidazolyl functional groups (one at either end of the molecules). Therefore, in some embodiments, the present invention is directed to a planar tertiary structure and indoles/furan rings that are substituted with two ionizable imidazolyl functional groups.
  • NSC 240898 and NSC 34190 have been found to inhibit botulinum neurotoxin serotype A light chain metalloprotease activity.
  • Various compounds of the present invention including NSC 240898, NSC 266474, NSC 266476, NSC 290107, NSC 290108, NSC 290109, NSC 294200, NSC 294201, NSC 294203, NSC 294204, NSC 294206, NSC 300511, NSC 308571, NSC 308572, NSC 308574, NSC 317880, NSC 317881, NSC 317884, NSC 317885, 317886, NSC 317887, NSC 341907, NSC 341909, and NSC 34191 1 are also found to inhibit the protease activity of anthrax lethal factor.
  • the compounds of the present invention may be used as broad spectrum antibiotics that may provide rapid and effective treatment by eliminating the need to identify the bacterial strain before treatment can be administered.
  • the compounds of the present invention may be used to prevent, inhibit or reduce the growth and spread of bacteria.
  • the compounds of the present invention may be used prophylactically, i.e. administered to a subject prior to exposure or likely exposure to bacteria or bacterial toxins.

Abstract

Disclosed herein are methods of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain which comprises contacting the bacteria with the compounds disclosed herein. Also disclosed are methods of treating, inhibiting or preventing an infection or intoxication caused by bacteria of at least one bacterial strain in a subject and pharmaceutical and cosmetic compositions comprising the compounds disclosed herein.

Description

BROAD SPECTRUM ANTIBACTERIAL COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS [01] This application claims the benefit of U.S. Provisional Patent Application
Serial Nos. 60/707,531, filed 12 August 2005, and 60/723,442, filed 5 October 2005, both of which are herein incorporated by reference in their entirety.
ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT
[02] This invention was made by employees of the United States Army Medical
Research and Materiel Command, which is an agency of the United States Government. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
1. FIELD OF THE INVENTION.
[03] The present invention relates to compounds which exhibit antibacterial properties.
2. DESCRIPTION OF THE RELATED ART.
[04] Acquired or engineered bacterial resistance to existing antibiotics represents one of the most significant obstacles to protecting both military personnel and civilians from harmful infections. The human induced evolution of bacterial strains resistant to amoxicillin, trimethoprim-sulfamethoxazole, penicillin, and methicillin has been well documented by the medical community, and it is increasingly evident that such microorganisms pose a major threat to public health. However, the most alarming threat to date is the emergence of bacteria that are resistant to vancomycin, the antibiotic that is the last line of defense in the clinic. Furthermore, it is clear that resistance is more likely when newly introduced antibiotics are chemically similar to those that are already ineffective. For example, the emergence of penicillin G resistance was followed by resistance to a structurally similar compound, amoxicillin.
[05] Thus, new antimicrobial compounds possessing novel scaffolds and unique mechanisms of action, are urgently needed.
SUMMARY OF THE INVENTION
[06] The present invention relates to compounds which exhibit antibacterial properties. [07] Specifically, the compounds of the present invention have the following structural formula:
Figure imgf000003_0001
wherein n is 1 or 2;
X1, X2, X3, X4, X5 and X6 are each independently N, S, O, SO2, CR7 or NR8 and at least one of X1 or X2 is N, S, O, SO2, or NR8;
L is a linker which may be a direct bond or ^ ^ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
R1, R2, R3, R4, R5, R6 and R7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 290111 , NSC 302569, and NSC 308569. In some embodiments, at least one of R1, R2, R3, or R4 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine. In some embodiments, R5 is hydrogen, amidine, 2- imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, methylamine- guanidine, 4-oxy-benzamidine, lH-indole-6-caboxamidine, or lH-indole-5- carboxamidine. In some embodiments, R6 is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl- imidazoline, benzofuran-2-yl-amidine, benzofuran-2-yl-guanidine, benzothiophene-2- yl-imidazoline, benzothiophene-2-yl-amidine, benzene-2-yl-amidine, benzofuran-2- yl-imidazole, or benzofuran-2-yl-oxazole. In some embodiments, at least one of X1 or X2 is N, NH, S, O, SO2, CH, C-CH3, C-phenyl, N-ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5-amidine). In some embodiments, at least one of X3, X4, X5, or X6 is N, NH, S, O, SO2, or CH. In some embodiments, at least one of R1, R2, R3, R4, R5, R6, or
R7 is -H, -CH3, -NH2,
Figure imgf000004_0001
Figure imgf000004_0002
. In some embodiments, R is -NH2,
Figure imgf000004_0003
. In some embodiments, R is -H, -CH3, -NH2,
Figure imgf000004_0004
, or . In some embodiments, R8 is -H, -(CH2)2θH, or -(CH2)2C1. In some embodiments, L is a direct bond,
Figure imgf000005_0001
has the following structural formulae:
Figure imgf000005_0002
Figure imgf000006_0001
In some embodiments, the compound is NSC 92833, NSC 103699, NSC 103701, NSC 130681, NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240896, NSC 240897, NSC 240898, NSC 240899, NSC 240900, NSC 266472, NSC 266474, NSC 266475, NSC 266476, NSC 266477, NSC 266482, NSC 278995, NSC 278996, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290109, NSC 291103, NSC 294199, NSC 294200, NSC 294201, NSC 294202, NSC 294203, NSC 294204, NSC 294206, NSC 294207, NSC 294208, NSC 294494, NSC 300509, NSC 300510, NSC 300511, NSC 300512, NSC 308570, NSC 308571, NSC 308572, NSC 308573,.NSC 308574, NSC 317880, NSC 317881, NSC 317883, NSC 317884, NSC 317885, NSC 317886, NSC 317887, NSC 330687, NSC 330688, NSC 330689, NSC 330690, NSC 341082, NSC 341907, NSC 341909, NSC 341910, NSC 341911, NSC 352341, NSC 369718, NSC 369721, NSC 607617, or NSC 12155. In some embodiments, the compound is NSC 317880, NSC 317881, NSC 330687, or NSC 369718.
[08] In some embodiments, the present invention provides a method of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain which comprises contacting the bacteria with an effective amount of at least one compound provided herein. In some embodiments, the bacterial strain is belongs to Bacillus, Burkholderia, Enterobacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia, or drug resistant strains thereof. In some embodiments, the bacterial strain is B. anthracis, B. brevis, B. licheniformis, B. megaterium, B. pumilus, B. subtilis, B. vollum, B. cepacia, B. mallei, M. pseudomallei, B. thailandensis, E. coli, E. feacalis, E. faecium, K. pneumoniae; P. aeruginosa, S. aureous, Y. pestis, or drug resistant strains thereof. In some embodiments, the bacteria are of two or more bacterial strains. In some embodiments, the bacteria are on or in an object, such as clothing, a table top, eating utensils, water, food, air, or anything which may come into contact with or may be consumed by a mammal such as a human. [09] In some embodiments, the present invention provides a method of treating, inhibiting or preventing an infection or intoxication caused by bacteria of at least one bacterial strain in a subject which comprises administering to the subject a therapeutically effective amount of at least one compound provided herein. In some embodiments, the bacterial strain is belongs to Bacillus, Burkholderia, Enter obacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia, or drug resistant strains thereof. In some embodiments, the bacterial strain is B. anthracis, B. brevis, B. licheniformis, B. megaterium, B. pumilus, B. subtilis, B. vollum, B. cepacia, B. mallei, M. pseudomallei, B. thailandensis, E. coli, E. feacalis, E. faecium, K. pneumoniae; P. aeruginosa, S. aureous, Y. pestis, or drug resistant strains thereof. In some embodiments, the bacteria are of two or more bacterial strains. In some embodiments, the compound is in the form of a pharmaceutical or cosmetic composition. In some embodiments, a supplementary active compound is administered to the subject. The supplementary active compound may be formulated with a compound of the present invention or provided as a separate composition.
[10] Both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed. The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of this specification, illustrate several embodiments of the invention, and together with the description serve to explain the principles of the invention.
DESCRIPTION OF THE DRAWINGS
[11] This invention is further understood by reference to the drawings wherein:
[12] Figure IAl shows a phase contrast image of GFP-sterne spores that were treated with a DMSO control and the growth of vegetative cells after 22 hours. [13] Figure 1 A2 shows a GFP fluorescence image of GFP-sterne spores that were treated with a DMSO control and the growth of vegetative cells after 22 hours. [14] Figure IBl shows a phase contrast image of GFP sterne spores treated with
NSC 317881 (MIC of 0.084 μg/ml) for 22 hours. [15] Figure 1B2 shows a GFP fluorescent image of GFP sterne spores treated with
NSC 317881 (MIC of 0.084 μg/ml) for 22 hours. [16] Figure 1 C is a graph showing time dependent inhibition of GFP fluorescence by a few compounds of the present invention at their MIC concentrations. [17] Figure ID is a graph showing growth inhibition of GFP sterne vegetative cells at different concentrations of a few compounds of the present invention. [18] Figure 2 is a graph which shows that NSC 317881 does not have any observable effect on sterne spore germination. [19] Figure 3 is a graph which shows that NSC 317881 kills GFP sterne spores in a time dependent manner. [20] Figure 4 shows the structural formulas of NSC 317880, NSC 317881, NSC
330687, and NSC 369718.
DETAILED DESCRIPTION OF THE INVENTION
[21] The present invention is directed to the antibacterial properties of bi- and triarylimidazoiidines and bi- and triarylamidines. The compounds of the present invention do not structurally resemble any of the current classes of clinically used antibiotics, including penicillins, cephalosporins, monobactams, carbapenems, fluoroquinolones, macrolides, aminoglycosides, streptogramins, oxazolidinones, metronidazole, clindamycin, and vancomycin. The compounds of the present invention are active against a broad range of gram positive and gram negative bacteria, including drug resistant strains such as vancomycin resistant enterococcus, methicillin resistant Staphylococcus aureus (MRSA) and ciproflaxcin resistant B. anthracis. As provided herein, some of the compounds of the present invention exhibit MIC values ranging from about 0.021 to about 22 μg/ml. Some of the compounds exemplified herein inhibit the outgrowth of B. anthracis spores and kill B. anthracis vegetative spores in the early stages of germination.
[22] The compounds of the present invention have the following Structural
Formula I: where Y is
Figure imgf000009_0001
Figure imgf000009_0002
wherein n is 1 or 2;
X1, X2, X3, X4, X5 and X6 are each independently N, S, O, SO2, CR7 or NR8 and at least one of X1 or X2 is N, S, O, SO2, or NR8;
L is a linker which may be a direct bond or ^ ^ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
R1, R2, R3, R4, R5, R6 and R7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 290111 , NSC 302569, and NSC 308569.
[23] It is noted that in the structural formulas of the present invention, the bond orders of the specified rings may vary when the various heteroatoms introduce specific requirements to satisfy aromaticity, prevent antiaromaticity, and stabilize tautomeric forms due to localization. Thus, the appropriate bond orders of the ring structures in the structural formulas of the present invention are contemplated herein.
[24] In some embodiments, R1 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine.
[25] In some embodiments, R2 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine. [26] In some embodiments, R3 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine. [27] In some embodiments, R4 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine-guanidine.
[28] In some embodiments, R5 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, methylamine-guanidine, 4-oxy- benzamidine, lH-indole-6-caboxamidine, or lH-indole-5-carboxamidine.
[29] In some embodiments, R6 is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl- imidazoline, benzofuran-2-yl-amidine, benzofuran-2-yl-guanidine, benzothiophene-2- yl-imidazoline, benzothiophene-2-yl-amidine, benzene-2-yl-amidine, benzofuran-2- yl-imidazole, or benzofuran-2-yl-oxazole.
[30] In some embodiments, X1 is N, NH, S, O, SO2, CH, C-CH3, C-phenyl, N- ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5 -amidine).
[31] In some embodiments, X2 is N, NH, S, O, SO2, CH, C-CH3, C-phenyl, N- ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6-amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5-amidine).
[32] In some embodiments, X3 is N, NH, S, O, SO2, or CH.
[33] In some embodiments, X4 is N, NH, S, O, SO2, or CH.
[34] In some embodiments, X5 is N, NH, S, O, SO2, or CH.
[35] In some embodiments, X6 is N, NH, S, O, SO2, or CH.
[36] In some embodiments, at least one of R1, R2, R3, R4, R5, R6 or R7 is -H, -CH3,
Figure imgf000010_0001
[37] In some embodiments, R is -NH2,
Figure imgf000011_0001
H,
J
[38] I
Figure imgf000011_0002
n some embodiments, R is or
Figure imgf000011_0003
[39] In some embodiments, R7 is -H, -CH3, -NH2,
Figure imgf000011_0004
Figure imgf000011_0005
[40] In some embodiments, R8 is -H, -(CH2)2OH, or -(CH2)2C1.
[41] In some embodiments, L is a direct bond,
Figure imgf000012_0001
Figure imgf000012_0002
[42] In some embodiments, compounds of the present invention have the following structural formulae:
Figure imgf000012_0003
Figure imgf000013_0001
wherein n is 1 or 2;
X1, X2, X3, X4, X5 and X6 are each independently N, S, O, SO2, CR7 or NR8 and at least one of X1 or X2 is N, S, O, SO2, or NR8;
L is a linker which may be a direct bond or ^ ^ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
R1, R2, R3, R4, R5, R6 and R7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 2901 11, NSC 302569, and NSC 308569.
[43] In accordance with a convention used in the art, \ /£ ** is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
[44] Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both sterioisomeric forms are intended to be encompassed.
[45] A "halo" or "halogen" means fluorine, bromine, chlorine, and iodine.
[46] An "alkyl" is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (n-Bu), isobutyl (i-Bu), t- butyl (t-Bu), (sec-Bu), and the like, which may be unsubstituted (i.e., contain only carbon and hydrogen) or substituted by one or more suitable substituents as defined below. A "lower alkyl group" is intended to mean an alkyl group having from 1 to 8 carbon atoms in its chain.
[47] A "haloalkyl" refers to an alkyl that is substituted with one or more same or different halo atoms, e.g., -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, and the like.
[48] An "alkenyl" means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one double bond such as ethenyl, 3-buten-l-yl, 2- ethenylbutyl, 3-hexen-l-yl, and the like. The term "alkenyl" includes, cycloalkenyl, and heteroalkenyl in which 1 to 3 heteroatoms selected from O, S, N or substituted nitrogen may replace carbon atoms.
[49] An "alkynyl" means straight and branched hydrocarbon radicals having from 2 to 8 carbon atoms and at least one triple bond and includes, but is not limited to, ethynyl, 3-butyn-l-yl, propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, and the like.
[50] A "cycloalkyl" is intended to mean a non-aromatic monovalent monocyclic or polycyclic radical having from 3 to 14 carbon atoms, each of which may be saturated or unsaturated, and may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be unsubstituted or substituted by one or more substituents. Examples of cycloalkyl groups include cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl.
[51] A "heterocycloalkyl" is intended to mean a non-aromatic monovalent monocyclic or polycyclic radical having 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be unsubstituted or substituted by one or more substituents. Examples of heterocycloalkyl groups include oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholinyl.
[52] An "aryl" (Ar) is intended to mean an aromatic monovalent monocyclic or polycyclic radical comprising generally between 5 and 18 carbon ring members, which may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Thus, the term "aryl group" includes a benzyl group (BzI). Examples include phenyl, biphenyl, 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl, and phenanthryl. [53] A "heteroaryl" is intended to mean an aromatic monovalent monocyclic or polycyclic radical comprising generally between 4 and 18 ring members, including 1-
5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Examples include thienyl, furanyl, thiazolyl, triazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrrolyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl, pyrimidinyl, isoquinolinyl, quinolinyl, napthyridinyl, phthalimidyl, benzimidazolyl, and benzoxazolyl. [54] A "hydroxy" is intended to mean the radical -OH.
[55] An "alkoxy" is intended to mean the radical -OR, where R is an alkyl group.
Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. [56] A "hydroxyalkyl" means an alkyl that is substituted with one, two, or three hydroxy groups, e.g. hydroxy methyl, 1 or 2-hydroxyethyl, 1,2-, 1,3-, or 2,3- dihydroxypropyl, and the like. [57] A "haloalkoxy" refers to an -O-(haloalkyl) group. Examples include trifluoromethoxy, tribromomethoxy, and the like. [58] A "cycloalkoxy" is intended to mean the radical -OR, where R is acycloalkyl or heterocycloalkyl group. [59] An "aryloxy" is intended to mean the radical -OR, where R is an aryl or heteroaryl group. Examples include phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like. [60] An "acyl" is intended to mean a -C(O)-R radical, where R is an alkyl or aryl, bonded through a carbonyl group. Acyl groups include acetyl, benzoyl, and the like. [61] An "aralkyl" means an alkyl that is substituted with an aryl group. Examples include -CH2-phenyl, -(CH2)2-phenyl, -(CH2)3-phenyl, -CH3CH(CH3)CH2-phenyl, and the like. [62] A "heteroaralkyl" group means an alkyl that is substituted with a heteroaryl group. Examples include -CH2-pyridinyl, -(CH2)2-pyrimidinyl, -(CH2)3-imidazolyl, and the like. [63] A "carboxy" is intended to mean the radical -C(O)OH. [64] An "alkoxycarbonyl" is intended to mean the radical -C(O)OR, where R is an alkyl group. Examples include methoxycarbonyl, ethoxycarbonyl, and the like.
[65] An "amino" is intended to mean the radical -NH2.
[66] An "amine with stabilized carbocations" are comprised of two or more NH2 groups that contribute lone pairs to configure a highly stabilized carbocation. Examples include amidines and guanidines.
[67] An "alkylamino" is intended to mean the radical -NHR, where R is an alkyl group or the radical -NRaRb, where Ra and Rb are each independently an alkyl group. Examples of alkylamino groups include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N- isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino, N- n-hexyl-N-methylamino and the like.
[68] An "alkylsulfhydryl" is intended to mean R-SH, where R is an alkyl group.
Examples include methylsulfhydryl, ethylsulfhydryl, n-propylsulfhydryl, iso- propylsulfhydryl, n-butylsulfhydryl, iso-butylsulfhydryl, secondary-butylsulfhydryl, tertiary -butylsulfhydryl. Preferable alkylsulfhydryl groups are methylsulfhydryl, ethylsulfhydryl, n-propylsulfhydryl, n-butylsulfhydryl, and the like.
[69] An "alkylhydroxymate" is intended to mean the radical R-C(O)NH-OH, where R is an alkyl group. Examples include methylhydroxymate, ethylhydroxymate, n-propylhydroxymate, iso-propylhydroxymate, n-butylhydroxymate, iso- butylhydroxymate, secondary-butylhydroxymate, tertiary-butylhydroxymate. Preferable alkylhydroxymate groups are methylhydroxymate, ethylhydroxymate, n- propylhydroxymate, n-butylhydroxymate, and the like.A "carbamoyl" is intended to mean the radical -C(O)NH2.
[70] An "alkylaminocarbonyl" is intended to mean the radical -C(O)NHR, where
R is an alkyl group or the radical -C(0)NRaRb, where Ra and Rb are each independently an alkyl group. Examples include methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, methylethylaminocarbonyl, and the like.
[71] A "mercapto" is intended to mean the radical -SH.
[72] An "alkylthio" is intended to mean the radical -SR, where R is an alkyl or cycloalkyl group. Examples of alkylthio groups include methylthio, ethylthio, n- propylthio, isopropylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
[73] An "arylthio" is intended to mean the radical -SR, where R is an aryl or heteroaryl group. Examples include phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
[74] A "thioacyl" is intended to mean a -C(S)-R radical, where R is an alkyl or aryl, bonded through a thiol group.
[75] An "alkylsulfonyl" is intended to mean the radical -SO2R, where R is an alkyl group. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso- propylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, secondary-butylsulfonyl, tertiary- butylsulfonyl. Preferable alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, n-butylsulfonyl, and the like.
[76] A "leaving group" (Lv) is intended to mean any suitable group that will be displaced by a substitution reaction. One of ordinary skill in the art will know that any conjugate base of a strong acid can act as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p- toluenesulfonates, alkyl methanesulfonates, triflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion.
[77] A "protecting group" is intended to refer to groups that protect one or more inherent functional group from premature reaction. Suitable protecting groups may be routinely selected by those skilled in the art in light of the functionality and particular chemistry used to construct the compound. Examples of suitable protecting groups are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York, New York (1999).
[78] The term "suitable organic moiety" is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxyl groups, carboxyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like. [79] In general, the various moieties or functional groups for variables in the formulae may be "optionally substituted" by one or more suitable "substituents". The term "substituent" or "suitable substituent" is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Illustrative examples of useful substituents are those found in the exemplary compounds that follow, as well as a halogen; C1-6-alkyl; C^-alkenyl; Ci-6-alkynyl; hydroxyl; Q-6 alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; carbonyl; aminocarbohyl; thiocarbonyl; sulfonyl; sulfonamine; sulfonamide; ketone; aldehyde; ester; oxygen (=0); haloalkyl (e.g. , trifluoromethyl); carbocyclic cycloalkyl, which may be monocyclic or fused or non- fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether, 0-lower alkyl; O-aryl, aryl; aryl-lower alkyl; CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and the like. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH2-O. All of these substituents may optionally be further substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroarylthio groups, and the like.
[80] The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted). [81] It is understood that while a compound of the general structural formulas herein may exhibit the phenomenon of tautomerism, the structural formulas within this specification expressly depict only one of the possible tautomeric forms. It is therefore to be understood that the structural formulas herein are intended to represent any tautomeric form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formulas.
[82] It is also understood that the structural formulas are intended to represent any configurational form of the depicted compound and is not to be limited merely to a specific compound form depicted by the structural formulas.
[83] Some of the compounds of the present invention may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, or mixtures of enantiomers, diastereomers, or both when they contain one or more stereogenic centers as designated by R or S according to the Cahn-Ingold-Prelog rules whether the absolute or relative configuration is known. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
[84] Some of the compounds in the present invention may exist as geometric isomers as the result of containing a stereogenic double bond. In such cases, they may exist either as pure or mixtures of cis or trans geometric isomers or (E) and (Z) designated forms according to the Cahn-Ingold-Prelog rules and include compounds that adopt a double bond configuration as a result of electronic derealization.
[85] As generally understood by those skilled in the art, an optically pure compound having one or more chiral centers (i.e., one asymmetric atom producing unique tetrahedral configuration) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. If the compounds of the present invention are made synthetically, they may be used in a form that is at least 90% optically pure, that is, a form that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
[86] Additionally, the structural formulas herein are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone. Also included are miscible formulations of solvate mixtures such as a compound of the invention in combination with an acetone and ethanol mixture. In a preferred embodiment, the solvate includes a compound of the invention in combination with about 20% ethanol and about 80% acetone. Thus, the structural formulas include compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.
[87] As indicated above, the compounds of the invention also include active tautomeric and stereoisomeric forms of the compounds of the present invention, which may be readily obtained using techniques known in the art. For example, optically active (R) and (S) isomers may be prepared via a stereospecific synthesis, e.g., using chiral synthons and chiral reagents, or racemic mixtures may be resolved using conventional techniques.
[88] Additionally, the compounds of the invention include pharmaceutically acceptable salts, multimeric forms, prodrugs, active metabolites, precursors and salts of such metabolites of the compounds of the present invention.
[89] The term "pharmaceutically acceptable salts" refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being treated with the compound of the invention. Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid. Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g. , sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from non-toxic organic bases such as basic amino acids.
[90] The term "multimer" refers to multivalent or multimeric forms of active forms of the compounds of the invention. Such "multimers" may be made by linking or placing multiple copies of an active compound in close proximity to each other, e.g., using a scaffolding provided by a carrier moiety. Multimers of various dimensions (i.e., bearing varying numbers of copies of an active compound) may be tested to arrive at a multimer of optimum size with respect to binding site interactions. Provision of such multivalent forms of active binding compounds with optimal spacing between the binding site moieties may enhance binding site interactions. See e.g. Lee et al., (1984) Biochem. 23:4255. The artisan may control the multivalency and spacing by selection of a suitable carrier moiety or linker units. Useful moieties include molecular supports comprising a multiplicity of functional groups that can be reacted with functional groups associated with the active compounds of the invention. A variety of carrier moieties may be used to build highly active multimers, including proteins such as BSA (bovine serum albumin), peptides such as pentapeptides, decapeptides, pentadecapeptides, and the like, as well as non-biological compounds selected for their beneficial effects on absorbability, transport, and persistence within the target organism. Functional groups on the carrier moiety, such as amino, sulfhydryl, hydroxyl, and alkylamino groups, may be selected to obtain stable linkages to the compounds of the invention, optimal spacing between the immobilized compounds, and optimal biological properties.
[91] "A pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound, or a compound that is biologically active with respect to the intended pharmacodynamic effect. "A pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art See, e.g., Bertolini, G. et ah, (1997) J. Med. Chem. 40:2011-2016; Shan, D. et al, J. Pharm. Set, 86(7):765-767; Bagshawe K., (1995) Drug Dev. Res. 34:220-230; Bodor, N., (1984) Advances in Drug Res. 13:224- 331; Bundgaard, R, Design of Prodrugs (Elsevier Press, 1985); and Larsen, I. K., Design and Application of Prodrugs, Drug Design and Development (Krogsgaard- Larsen et al, eds., Harwood Academic Publishers, 1991).
[92] If the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an α- hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
[93] If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from basic amino acids, such as lysine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[94] In the case of compounds that are solids, it is understood by those skilled in the art that the compound of the present invention and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified structural formulas.
[95] The compounds of the present invention are useful in inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain. The compounds of the present invention are also treating, inhibiting or preventing an infection or intoxication caused by bacterial of at least one bacterial strain in a subject. The bacteria belong to various gram positive and gram negative bacteria strains including Bacillus, Burkholderia, Enterobacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia and the like, including drug resistance strains. In preferred embodiments, the bacteria is B. anthracis (including Ames strain and ciprofloxacin resistant Ames strain) B. anthlO24 (K1021), B. brevis, B. licheniformis, B. megaterium, B. pumilus, B. subtilis, B. vollum, and spores thereof; B. cepacia, B. mallei, M. pseudomallei, and B. thailandensis; E. coli, E. feacalis, E. faecium, and vancomycin resistant strains thereof; K. pneumoniae; P. aeruginosa, preferably PAOl; & aureus and methicillin resistant S. aureous; Y. pestis; or a combination thereof.
[96] The activity of the compounds of the present invention may be measured by any of the methods available to those skilled in the art, including in vitro and in vivo assays. Examples of suitable assays for activity measurements are provided herein. Properties of the compounds of the present invention may be assessed, for example, by using one or more of the assays set out in the Examples below. Other pharmacological methods may also be used to determine the efficacy of the compounds a subject suffering from a given disease or disorder. The compounds of the present invention may be used in combination with or as a substitution for treatments known in the art.
[97] The therapeutically effective amounts of the compounds of the invention for treating the diseases or disorders described above in a subject can be determined in a variety of ways known to those of ordinary skill in the art, e.g. by administering various amounts of a particular compound to a subject afflicted with a particular condition and then determining the effect on the subject. Typically, therapeutically effective amounts of a compound of the present invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect. It will be understood, however, that the specific dose levels for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease.
[98] Frequency of dosage may also vary depending on the compound used and the particular disease treated It will also be appreciated that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances chronic administration may be required. The compounds of the present invention may be administered before, during, after, or a combination thereof exposure to bacteria.
[99] As provided herein, an "effective amount" is intended to mean that amount of a compound that is sufficient to reduce, prevent or inhibit bacterial growth as compared with a negative control. A "therapeutically effective amount" of a compound of the present invention, a prodrug, an active metabolite, or a salt thereof, is a quantity sufficient to, when administered to a subject, reduce, prevent or inhibit bacterial growth. Also, as used herein, a "therapeutically effective amount" of a compound of the present invention is an amount which prevents, inhibits, suppresses, or reduces a given clinical condition in a subject as compared to a control. As defined herein, a therapeutically effective amount of a compound of the present invention may be readily determined by one of ordinary skill by routine methods known in the art.
[100] The pharmaceutical formulations of the invention comprise at least one compound of the present invention and may be prepared in a unit-dosage form appropriate for the desired mode of administration. The pharmaceutical formulations of the present invention may be administered for therapy by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), dermal, mucosal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen compound of the present invention.
[101] The compound can be administered alone, but will generally be administered as pharmaceutical formulations suitable for administration. Pharmaceutical formulations known in the art contemplated herein. Pharmaceutical formulations of this invention comprise a therapeutically effective amount of at least one compound of the present invention, and an inert, pharmaceutically or cosmetically acceptable carrier or diluent. As used herein the language "pharmaceutically acceptable carrier" or a "cosmetically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical or cosmetic administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the formulation is contemplated. Descriptions of suitable pharmaceutically acceptable carriers, formulations, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
[102] Supplementary active compounds can also be incorporated into the formulations. Supplementary active compounds include antibiotics, antiprotozoal agents, antifungal agents, and antiproliferative agents known in the art, analgesics and other compounds commonly used to treat diseases and disorders associated with bacterial infection and toxic side effects of bacterial infection including intoxication by a toxin.
[103] Antibiotics include penicillin, cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, ampicillin, amoxicillin, bacampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, azithromycin, clarithromycin, clindamycin, erythromycin, lincomycin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, quinolone, cinoxacin, nalidixic acid, fluoroquinolone, ciprofloxacin, enoxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, sulfonamide, trimethoprim- sulfamethoxazole, co-amoxyclav, cephalothin, cefuroxime, ceftriaxone, vancomycin, gentamicin, amikacin, metronidazole, chloramphenicol, nitrofurantoin, co- trimoxazole, rifampicin, isoniazid, pyrazinamide, kirromycin, thiostrepton, micrococcin, fusidic acid, thiolactomycin, fosmidomycin, and the like.
[104] Antiprotozoal agents include chloroquine, doxycycline, mefloquine, metronidazole, eplornithine, furazolidone, hydroxychloroquine, iodoquinol, pentamidine, mebendazole, piperazine, halofantrine, primaquine, pyrimethamine sulfadoxine, doxycycline, clindamycin, quinine sulfate, quinidine gluconate, quinine dihydrochloride, hydroxychloroquine sulfate, proguanil, quinine, clindamycin, atovaquone, azithromycin, suramin, melarsoprol, eflornithine, nifurtimox, amphotericin B, sodium stibogluconate, pentamidine isethionate, trimethoprim- sulfamethoxazole, pyrimethamine, sulfadiazine, and the like.
[105] Antifungal agents include amphotericin B, fluconazole, itraconazole, ketoconazole, potassium iodide, flucytosine, and the like.
[106] Antiproliferative agents such as altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bleomycin, busulfan, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cisplatin-epinephrine gel, cladribine, cytarabine liposomal, daunorubicin liposomal, daunorubicin daunomycin, dexrazoxane, docetaxel, doxorubicin, doxorubicin liposomal, epirubicin, estramustine, etoposide phosphate, etoposide VP- 16, exemestane, fludarabine, fluorouracil 5-FU, fulvestrant, gemicitabine, gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea, idarubicin, ifosfamide, imatinib mesylate, irinotecan, letrozole, leucovorin, levamisole, liposomal daunorubicin, melphalan L-PAM, mesna, methotrexate, methoxsalen, mitomycin C, mitoxantrone, paclitaxel, pamidronate, pegademase, pentostain, porfimer sodium, streptozocin, talc, tamoxifen, temozolamide, teniposide VM- 26, topotecan, toremifene, tretinoin, ATRA, valrubicin, vinorelbine, zoledronate, steroids, and the like.
[107] Supplementary active compounds also include those which inhibit botulinum neurotoxin serotype A light chain metalloprotease activity, anthrax lethal factor protease activity, and other bacterial toxins and proteases known in the art.
[108] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
[109] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. High throughput screening of small molecules against GFP-sterne spores and vegetative cells
[110] To examine the effect of small molecule compounds on B. anthracis spores and vegetative cells, the sterne strain that endogenously expresses green fluorescent protein was used. See Burnett, et al. (2005) Nat Rev. Drug Discov. 4:281-297, which is herein incorporated by reference. The sterne strain contains the pXOl plasmid that produces the anthrax toxins but it does not produce the capsule, as it does not contain the pXO2 plasmid. A total of 71 compounds from National Cancer Institute's open repository were screened at concentrations ranging from 40 μM to 0.03 μM against heat activated, ungerminated GFP sterne spores and vegetative cells. GFP fluorescence measurements using methods known in the art were taken at different time intervals. Figure 1 shows the results of a few compounds that were tested on heat activated, ungerminated GFP sterne spores and vegetative cells.
[Ill] Figure IAl shows GFP sterne spores treated with DMSO (control) germinated and produced long rod shaped bacteria which exhibited GFP fluorescence as provided in Figure 1 A2. By contrast, Figures IBl and 1B2 show that the compounds of the present invention inhibited the outgrowth of the sterne spores. Specifically, Figure IBl shows a loss in spore refractility and Figure 1B2 shows increasing phase dark, thereby suggesting that the sterne spores germinated; however, the bacteria failed to outgrow. This outgrowth inhibition was further confirmed by a fluorescence plate reader assay known in the art.
[112] The fluorescence plate reader assay showed no increase in GFP fluorescence as compared to a control as provided in Figure 1C. The dose dependent effects of a few compounds of the present invention on GFP expressing vegetative cells is shown in Figure ID. A list of 71 different compounds screened, along with their minimum inhibitory concentration (MIC) values when tested on B. anthracis GFP sterne spores and vegetative cells, is summarized in Table 1.
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Screening of the most potent antibacterial compounds against both gram positive and gram negative bacteria To determine if the compounds were capable of acting against a broad spectrum of gram positive and gram negative bacteria, the four most potent from the screen against GFP sterne spores (NSC 317880, NSC 317881, NSC 330687, and NSC 369718) were tested at varying concentrations on 20 different bacterial strains. Visual inspections of the plates, as well as absorbance readings at OD6Oo, were taken to determine the MICs of the compounds. The MIC values of these four compounds against the different bacterial strains are provided in Table 2.
Table 2
MIC values of 4 compounds against selected gram positive and gram negative bacteria
NSC 317880 NSC 317881 NSC 330687 NSC 369718
Strain (μg/ml) (μg/ml) (μg/ml) (μg/ml)
Gram positive bacteria
B. anthracis Ames 0.584 0.32 1.103 1.392
Cipro resistant Ames 0.584 1.292 1.103 0.348
B. anth1024 1.168 0.162 0.551 0.348
*B. brevis 0.584 0.646 0.276 0.174
*B. licheniformis 2.335 0.646 2.206 1.392
*B. megaterium 0.584 0.323 0.551 0.348
*B. pumilus 0.146 0.021 0.138 0.348
*B. vollum 0.584 0.324 0.551 0.348
Ames spores 0.146 0.162 0.276 0.174
B. subtilis 0.292 0.162 0.551 0.348
S. aureus 1.168 0.323 1.10 0.696
*Methicillin resistant S. aureus 2.335 0.323 2.2 2.785
*E. feacalis 0.584 0.162 2.205 0.696
Vancomycin resistant E. faecium N.D 0.155 N.D N.D
Vancomycin resistant E. feacalis N.D 0.155 N.D N.D
Gram negative bacteria
*E. coli 0.584 0.646 1.10 1.392
*K. pneumoniae >18.68 10.34 >17.64 5.57
P. aeruginosa PA01 1.168 0.323 17.64 1.392
Y. pestis 18.68 20.68 8.82 1.392
*Burkholderia mallei 9.34 10.34 8.82 11.14
*Burkholderia pseudomallei 18.68 >20.68 > 17.64 2.785
HBurkholderia thailandensis 18.68 20.68 17.64 2.784
*B. cepacia 18.68 >20.68 4.41 22.28
*Clinical isolate ^Environment N. D - Not Determined
The effects of compounds on B. αnthrαcis spore germination 4] B. anthracis spores germinate within minutes following contact with a suitable medium, e.g. the moist tissue of the human respiratory system. Spore germination is usually detected in vitro by alterations in the spore refractility, heat resistance, and staining. Upon germination, spores will become non-refractile, increasing phase dark, susceptible to heat induced death, and stainable with dyes such as Wright-Giemsa stain. To determine the effects of the compounds on spore germination, NSC 317881 was selected for further study. Sterne spores were germinated in Muller Hinton medium in the presence of DMSO (control) or NSC 317881 (1 μM). At time intervals of 0, 15, and 30 minutes, samples were heated at 65 °C for 30 minutes and after cooling on ice, appropriate dilutions of the spores were plated on sheep blood agar plates. The next day, colonies were counted. The % survival was determined by comparing the colony count at different time points to that of the sample collected at time to. Figure 2 shows the percent survival plotted against time. [115] Spores treated with NSC 317881 were killed by heat within 15 minutes following their contact with suitable germination medium, thereby suggesting that spore germination is not affected by the compound. A loss in refractility (Figure IBl) further confirms the observation that the compound does not have an effect on spore germination. Likewise, NSC 317880, NSC 330687 and NSC 369718 were tested and results to those of NSC 317881 were obtained.
Time dependent killing of B. anthracis spores [116] Since the potent compounds had no effect on spore germination, but did inhibit outgrowth, NSC 317881 was examined for time dependent killing of sterne GFP spores. Sterne GFP spores were treated with DMSO (control) or NSC 317881 (1 μM), and at various time intervals appropriate dilutions of the spores were plated on sheep blood agar plates. Ther next day, colonies were counted, and percent reduction in colony forming units (cfu) as compared to the DMSO control was plotted. As shown in Figure 3, there was a considerable reduction in the cfu after about 60 minutes of treatment with the compound. No viable spores were detected after about a 4 hour treatment with the compound.
Determination of minimum bactericidal concentration (MBC) of the most potent bioactive compounds
[117] To determine if the identified bioactive compounds were bactericidal, several strains of gram positive bacteria were selected, including B. anthracis ciprofloxacin resistant Ames strains and B. anthracis Ames spores, and incubated for about 22 hours with different concentrations ranging from 0 μM to 10 μM of NSC 317881, NSC 317880, NSC 330687 and NSC 369718. Twenty-four hours later, bacteria from MIC wells and four wells above the MIC were plated on sheep blood agar plates. The next day, colony counts were made and MBC values that produced about a 99.9% reduction in viable count were determined using methods known in the art. The MBC values of NSC 317881, NSC 317880, NSC 330687 and NSC 369718 against the gram positive bacteria is provided in Table 3.
Table 3
MBCs of 4 compounds against selected gran i positive bacteria I
Gram positive bacteria NSC 317880 NSC 317881 NSC 330687 NSC 369718 (μg/ml) (μg/ml) (μg/ml) (μg/ml)
Cipro resistant Ames 1.168 1.292 4.41 0.348
B. anth1024 2.336 0.646 2.206 0.696
B.vollum 1.168 0.162 1.103 0.348
Ames spores 0.146 0.162 0.276 0.174
The MBC was defined as 1 :he lowest concentration that produced a 99.9% reduction in viable count
Structures of the most potent bioactive compounds The structural formulas of NSC 317880, NSC 317881, NSC 330687 and NSC
369718 are shown in Figure 4. The structural formulas of the other compounds provided in Table 1 may be obtained from NCBI Pubmed compound database at the world wide web at ncbi.nlm.nih.gov and other compound databases available in the art. Conformational analysis of a representative number of the compounds of the present invention indicate that the compounds favor a planar tertiary conformation, as the compounds are all highly conjugated systems. NSC 317880, NSC 317881 and NSC 330687 are often referred to as diarylimidazolines, as each possesses two indoles, with each of the indoles substituted with an imidazolyl at its six position. NSC 317880, NSC 317881 and NSC 330687 are a congeneric series that canvasses the structure-activity relationship of related structures. As provided in Table 2, the type of linker (see Structural Formula I) can result in structural differences that translate into large MIC variations from one bacterial species to another bacterial species. NSC 369718 is often referred to as a triarylimidazoline which comprises two indoles and one benzofuran. As with the other three compounds, the imidazolyl substitutions occur at the six positions. See Figure 4. In general, these compounds exhibit common structural features, including a planar tertiary structure and indoles/furan rings that are substituted with two ionizable imidazolyl functional groups (one at either end of the molecules). Therefore, in some embodiments, the present invention is directed to a planar tertiary structure and indoles/furan rings that are substituted with two ionizable imidazolyl functional groups.
[119] Various compounds of the present invention, including NSC 308574, NSC
341909, NSC 240898 and NSC 34190, have been found to inhibit botulinum neurotoxin serotype A light chain metalloprotease activity. Various compounds of the present invention, including NSC 240898, NSC 266474, NSC 266476, NSC 290107, NSC 290108, NSC 290109, NSC 294200, NSC 294201, NSC 294203, NSC 294204, NSC 294206, NSC 300511, NSC 308571, NSC 308572, NSC 308574, NSC 317880, NSC 317881, NSC 317884, NSC 317885, 317886, NSC 317887, NSC 341907, NSC 341909, and NSC 34191 1 are also found to inhibit the protease activity of anthrax lethal factor. Thus, not only is the present invention directed to methods of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain, such as Clostridium or Bacillus, preferably Clostridium botulinium or Bacillus anthracis, but it is also directed to methods of inhibiting toxin activity, such as botulinum neurotoxin serotype A light chain metalloprotease activity or the protease activity of anthrax lethal factor. The present invention is also directed to methods of treating a subject suffering from a bacterial infection or intoxication.
[120] Thus, the compounds of the present invention may be used as broad spectrum antibiotics that may provide rapid and effective treatment by eliminating the need to identify the bacterial strain before treatment can be administered. The compounds of the present invention may be used to prevent, inhibit or reduce the growth and spread of bacteria. Further, the compounds of the present invention may be used prophylactically, i.e. administered to a subject prior to exposure or likely exposure to bacteria or bacterial toxins.
[121] To the extent necessary to understand or complete the disclosure of the present invention, all publications, patents, and patent applications mentioned herein are expressly incorporated by reference therein to the same extent as though each were individually so incorporated.
[122] Having thus described exemplary embodiments of the present invention, it should be noted by those skilled in the art that the within disclosures are exemplary only and that various other alternatives, adaptations, and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.

Claims

We claim:
1. A method of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain which comprises contacting the bacteria with an effective amount of at least one compound having the following structural formula:
where Y is
Figure imgf000036_0001
Figure imgf000036_0002
wherein n is 1 or 2;
X1, X2, X3, X4, X5 and X6 are each independently N, S, O, SO2, CR7 or NR8 and at least one of X1 or X2 is N, S, O, SO2, or NR8;
(T -7 t^
L is a linker which may be a direct bond or ^ 1^ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
R1, R2, R3, R4, R5, R6 and R7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 290111, NSC 302569, and NSC 308569.
2. The method of claim 1, wherein at least one of R1, R2, R3, or R4 is hydrogen, amidine, 2- imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, or methylamine- guanidine.
3. The method of claim 1, wherein R5 is hydrogen, amidine, 2-imidazoline, amino, guanidine, methyl, aminomethyl-hydroxamine, methylamine-guanidine, 4-oxy-benzamidine, lH-indole- 6-caboxamidine, or lH-indole-5-carboxamidine.
4. The method of claim 1, wherein R6 is hydrogen, amidine, benzamidine, benzimidazoline, imidazoline, guanidine, imidazole, oxazole, benzofuran-2-yl-imidazoline, benzofuran-2-yl- amidine, benzofuran-2-yl-guanidine, benzothiophene-2-yl-imidazoline, benzothiophene-2-yl- amidine, benzene-2-yl-amidine, benzofuran-2-yl-imidazole, or benzofuran-2-yl-oxazole.
5. The method of claim 1, wherein at least one of X1 or X2 is N, NH, S, O, SO2, CH, C-CH3, C-phenyl, N-ethanol, N-chloroethyl, C-amino, C-(2-indole-6-imidazoline), C-(2-indole-6- amidine), C-(2-indole-5-imidazoline), or C-(2-indole-5-amidine).
6. The method of claim 1, wherein at least one of X3, X4, X5, or X6 is N, NH, S, O, SO2, or CH.
7. The method of claim 1, wherein at least one of R1, R2, R3, R4, R5, R6, or R7 is -H, -CH3, -
Figure imgf000037_0001
8. The method of claim 1, wherein R is -NH2,
Figure imgf000038_0001
Figure imgf000038_0002
9. The method o 6 - f claim 1, wherein R is
Figure imgf000038_0003
or
10. The method of claim 1, wherein R7 is -H, -CH3, -NH2,
Figure imgf000038_0004
, or
Figure imgf000038_0005
11. The method of claim 1, wherein R8 is -H, -(CH2)2OH, or-(CH2)2Cl.
2. The method of claim 1, wherein L is a direct bond,
Figure imgf000039_0001
Figure imgf000039_0002
13. The method of claim 1, wherein the compound has the following structural formulae:
Figure imgf000039_0003
14. A method of inhibiting, reducing or preventing growth of or destroying bacteria of at least one bacterial strain which comprises contacting the bacteria with an effective amount of at least one compound selected from the group consisting of NSC 92833, NSC 103699, NSC 103701, NSC 130681, NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240896, NSC 240897, NSC 240898, NSC 240899, NSC 240900, NSC 266472, NSC 266474, NSC 266475, NSC 266476, NSC 266477, NSC 266482, NSC 278995, NSC 278996, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290109, NSC 291103, NSC 294199, NSC 294200, NSC 294201, NSC 294202, NSC 294203, NSC 294204, NSC 294206, NSC 294207, NSC 294208, NSC 294494, NSC 300509, NSC 300510, NSC 300511, NSC 300512, NSC 308570, NSC 308571, NSC 308572, NSC 308573, NSC 308574, NSC 317880, NSC 317881, NSC 317883, NSC 317884, NSC 317885, NSC 317886, NSC 317887, NSC 330687, NSC 330688, NSC 330689, NSC 330690, NSC 341082, NSC 341907, NSC 341909, NSC 341910, NSC 341911, NSC 352341, NSC 369718, NSC 369721, NSC 607617, and NSC 12155.
15. The method of claim 1, wherein the compound is NSC 317880, NSC 317881, NSC 330687, or NSC 369718.
16. The method of claim 1, wherein the bacterial strain is belongs to Bacillus, Burkholderia, Enter obacter, Escherichia, Helicobacter, Klebsiella, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus, Streptococcus, Yersinia, or drug resistant strains thereof.
17. The method of claim 16, wherein the bacterial strain is B. anthracis, B. brevis, B. licheniformis, B. megaterium, B. pumilus, B. subtilis, B. vollum, B. cepacia, B. mallei, M. pseudomallei, B. thailandensis, E. coli, E. feacalis, E. faecium, K. pneumoniae; P. aeruginosa, S. aureous, Y. pestis, or drug resistant strains thereof.
18. The method of claim 1, wherein the bacteria are of two or more bacterial strains.
19. The method of claim 1 , wherein the compound is in the form of a pharmaceutical composition.
20. A method of treating, inhibiting or preventing an infection or intoxication caused by bacteria of at least one bacterial strain in a subject which comprises administering to the subject a therapeutically effective amount of at least one compound having the following structural formula:
where Y is
Figure imgf000041_0001
Figure imgf000041_0002
wherein n is 1 or 2;
X1, X2, X3, X4, X5 and X6 are each independently N, S, O, SO2, CR7 or NR8 and at least one of X1 or X2 is N, S, O, SO2, or NR8;
L is a linker which may be a direct bond or ^ ^ where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, or aryl, or C(O)NH; and
R1, R2, R3, R4, R5, R6 and R7 are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate;
R8 is hydrogen, OH, a halogen, or an optionally substituted alkyl; with the proviso that the compound is not NSC 290111, NSC 302569, and NSC 308569.
21. A method of treating, inhibiting or preventing an infection or intoxication caused by bacteria of at least one bacterial strain in a subject which comprises administering to the subject a therapeutically effective amount of at least one compound selected from the group consisting of NSC 92833, NSC 103699, NSC 103701, NSC 130681, NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240896, NSC 240897, NSC 240898, NSC 240899, NSC 240900, NSC 266472, NSC 266474, NSC 266475, NSC 266476, NSC 266477, NSC 266482, NSC 278995, NSC 278996, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290109, NSC 291103, NSC 294199, NSC 294200, NSC 294201, NSC 294202, NSC 294203, NSC 294204, NSC 294206, NSC 294207, NSC 294208, NSC 294494, NSC 300509, NSC 300510, NSC 300511, NSC 300512, NSC 308570, NSC 308571, NSC 308572, NSC 308573, NSC 308574, NSC 317880, NSC 317881, NSC 317883, NSC 317884, NSC 317885, NSC 317886, NSC 317887, NSC 330687, NSC 330688, NSC 330689, NSC 330690, NSC 341082, NSC 341907, NSC 341909, NSC 341910, NSC 341911, NSC 352341, NSC 369718, NSC 369721, NSC 607617, and NSC 12155.
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